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. 2009 Jan;85(1):146-53.
doi: 10.1189/jlb.0308161. Epub 2008 Oct 9.

"V体育平台登录" Mice with heterozygous deficiency of lipoic acid synthase have an increased sensitivity to lipopolysaccharide-induced tissue injury

Xianwen Yi  1 , Kuikwon Kim, Weiping Yuan, Longquan Xu, Hyung-Suk Kim, Jonathon W Homeister, Nigel S Key, Nobuyo Maeda
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VSports手机版 - Mice with heterozygous deficiency of lipoic acid synthase have an increased sensitivity to lipopolysaccharide-induced tissue injury

Xianwen Yi et al. J Leukoc Biol. 2009 Jan.

Abstract

Alpha-lipoic acid (1, 2-dithiolane-3-pentanoic acid; LA), synthesized in mitochondria by LA synthase (Lias), is a potent antioxidant and a cofactor for metabolic enzyme complexes. In this study, we examined the effect of genetic reduction of LA synthesis on its antioxidant and anti-inflammatory properties using a model of LPS-induced inflammation in Lias+/- mice. The increase of plasma proinflammatory cytokine, TNF-alpha, and NF-kappaB at an early phase following LPS injection was greater in Lias+/- mice compared with Lias+/+ mice. The circulating blood white blood cell (WBC) and platelet counts dropped continuously during the initial 4 h. The counts subsequently recovered partially in Lias+/+ mice, but the recovery was impaired totally in Lias+/- mice. Administration of exogenous LA normalized the recovery of WBC counts in Lias+/- mice but not platelets. Enhanced neutrophil sequestration in the livers of Lias+/- mice was associated with increased hepatocyte injury and increased gene expression of growth-related oncogene, E-selectin, and VCAM-1 in the liver and/or lung. Lias gene expression in tissues was 50% of normal expression in Lias+/- mice and reduced further by LPS treatment. Decreased Lias expression was associated with diminished hepatic LA and tissue oxidative stress. Finally, Lias+/- mice displayed enhanced mortality when exposed to LPS-induced sepsis. These data demonstrate the importance of endogenously produced LA for preventing leukocyte accumulation and tissue injury that result from LPS-induced inflammation VSports手机版. .

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Figures (V体育平台登录)

Fig. 1.
Fig. 1.
Plasma glucose, body temperature, and hematological indices in Lias+/– and Lias+/+ mice. (A) Plasma glucose concentration following LPS injection (i.p). (B) Body temperature. (C) White blood cell (WBC) count in circulating blood in Lias+/– mice versus Lias+/+ mice without supplementation of exogenous LA; *, P < 0.05. (D) WBC count in circulating blood in Lias+/– mice versus Lias+/+ mice with supplementation of LA (40 mg/kg body weight). (E) Platelet count in circulating blood and Lias+/– mice without supplementation of exogenous LA; ***, P < 0.001.
Fig. 2.
Fig. 2.
Liver and kidney injury at 8 and 24 h after i.p. injection of LPS. Effect of LPS on MPO activity in the lung (A) and liver (B). Solid bars represent Lias+/– mice, and open bars represent Lias+/+ mice. Error bars represent se, and numbers in the bars or above the bars indicate animal numbers for each group. (C) Activity of serum ALT and (D) activity of AST in Lias+/– and Lias+/+ mice. (E) BUN. The ALT, AST, and BUN results represent means sem of values obtained from seven mice per group. P values are determined using Tukey-Kramer’s HSD test.
Fig. 3.
Fig. 3.
Endogenous LA reduces the mortality of LPS-induced sepsis. LPS was injected i.p. in Lias+/– and Lias+/+ mice (eight mice per group). Survival rate was monitored during a subsequent 5-day period. The statistical significance of mortality and survival time was determined by the Kaplan-Meyer method.
Fig. 4.
Fig. 4.
Plasma levels of TNF-α (A), IL-10 (B), IL-6 (C), and MCP-1 (D) following LPS treatment. (○) Lias+/+ mice; (•) Lias+/– mice. **, P < 0.01, between Lias+/– and Lias+/+ mice at the time-point.
Fig. 5.
Fig. 5.
NF-κB activity in liver and lung nuclear extract at 1 h after LPS injection (4 mg/kg body weight) was determined by Trans-AM NF-κB ELISA kit for assay of NF-κB/p65. Bars represent mean ± sem of liver and lung of seven mice with LPS treatment and five mice with saline in each genotype. P < 0.001 for effects of LPS; P < 0.05 for genotype effects in liver by ANOVA.
Fig. 6.
Fig. 6.
LPS-induced oxidative stress. (A) TBARS in plasma. (B) Reduced GSH in erythrocytes. (C and D) TBARS and GSH in the liver and lung homogenates at 8 h after LPS injection. (E and F) TBARS and GSH levels in the Lias+/– liver and lung at 8 h after single-dose LA (40 mg/kg body weight) i.p. injection at 30 min following LPS administration. Twelve mice were injected with exogenous LA. (G) Plasma NOx before (0 h) and at 8 h after the LPS treatment. (H) NOx in the liver homogenates before and at 8 h after LPS treatment. Values are mean ± sem. Significance is determined using Tukey-Kramer’s HSD test. The numbers in the bars or above the bars indicate animal numbers. NS, No significance.
Fig. 7.
Fig. 7.
Lias gene expression. mRNA levels isolated from livers at 8 h after LPS administration for the Lias gene determined by quantitative real-time PCR. The data are expressed as the mean ± sem relative to the mean values of the levels in Lias+/+ mice without treatment as 1.0. Numbers in each bar indicate numbers of mice in each group. Solid bars indicate Lias+/– mice, and open bars represent Lias+/+ mice.
Fig. 8.
Fig. 8.
(A–D) LA content in tissue liver sections visualized by immunofluorescence (Texas Red) with a rabbit anti-LA polyclonal antibody in Lias+/+ (A and C) and Lias+/– (B and D), without (A and B) and with (C and D) LPS treatment. Original magnification, ×200 for all panels.
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